1. Field of the Invention
The present invention relates to a method of treating multidrug resistance with phosphodiesterase (PDE) inhibitors, e.g., PDE5 inhibitors. More specifically, the present invention relates to a method of treating multidrug resistance, e.g., multidrug resistance that arises, e.g., during administration of chemotherapeutic or antineoplastic agents for treatment of cancer, with a PDE5 inhibitor (e.g., vardenafil, sildenafil, and tadalafil). In addition, the invention relates to a method of treating cancer, e.g., multidrug resistant cancer, using a PDE5 inhibitor in combination with an anticancer agent, i.e., a chemotherapeutic/antineoplastic agent. Further, the invention relates to a pharmaceutical composition for treating a multidrug resistant cancer comprising a PDE5 inhibitor, or a combination of a PDE5 inhibitor and an antineoplastic agent.
2. Description of Related Art
Multidrug resistance (MDR) is a phenomenon in which disease-causing organisms or cells are able to evade treatment with drugs designed to target them. Multidrug resistance to cancer chemotherapy, a major hurdle to successfully treating cancer, commonly arises due to the ability of one or more cancer cells to resist treatment with a variety of agents, e.g., drugs that may be distinct in one or both of the following: structure and mechanism of action. Therefore, whereas a portion of cancer cells, i.e., drug-sensitive cancer cells, are killed with a chemotherapeutic agent, drug-resistant cancer cells survive, such that the resultant or remaining cancers consist primarily of drug-resistant (or medicine-tolerant) cells.
One known cause of multidrug resistance to cancer chemotherapy is the overexpression of ATP-binding cassette (ABC) transporters in the membranes of cancers cells (Szakacs et al. (2006) Nat. Rev. Drug Discov. 5:219-34). These pumps efflux agents, including structurally and functionally unrelated chemotherapeutic agents, out of cancer cells, significantly decreasing the chance of successful treatment. In mammals, the ABC transporters have been divided into seven subfamilies (i.e., subfamilies A-G), based on genome sequence similarities (Gottesman et al. (2002) Nat. Rev. Cancer 2:48-58.). Studies to date have consistently shown that the three major ABC transporters involved in multidrug resistance in most cancer cells are P-glycoprotein (Pgp/ABCB1/MDR1), breast cancer resistant protein (ABCG2/BCRP/ABCP), and members of the multidrug resistance protein family, e.g., multidrug resistant protein 1 (ABCC1/MRP1).
Overexpression of ABCB1 transporter occurs in 40-50% of all cancers; therefore, there is a major ongoing effort to design a strategy for inhibiting this transporter. Three generations of compounds that inhibit ABCB1 have been studied. The first generation of ABCB1 inhibitors included such drugs as verapamil, quinine, and cyclosporine A; however, these first generation agents produced undesirable adverse effects at concentrations necessary to inhibit ABCB1 (Krishna et al. (2000) Eur. J. Pharm. Sci. 11:265-83). The second generation of ABCB1 inhibitors, e.g., valspodar and biricodar, produced unpredictable interactions with other transport proteins and inhibited cytochrome P450 3A4 (CYP3A4), an enzyme responsible for metabolizing many xenobiotics, including chemotherapeutic drugs. Therefore, the use of the second generation ABCB1 inhibitors resulted in decreased clearance and increased toxicity of many chemotherapeutic agents (Gottesman et al., supra). The third generation of inhibitors, e.g., LY335979 (zosuquidar), GF120918 (elacridar), and MS-209 (dofequidar), were derived from second generation agents, and had nanomolar affinity for the ABCB1 transporter. However, to date third generation inhibitors have not been approved for use in patients due to several factors, including adverse side effects, unfavorable pharmacokinetic profiles, and/or lack of significant efficacy in late-phase clinical trials (Modok et al. (2006) Curr. Opin. Pharmacol. 6:350-54; Wu et al. (2009) Curr. Mol. Pharmacol. 1:93-105). Thus, it would be beneficial to determine whether other drugs, including drugs already used in the clinic, are capable of inhibiting ABC transporters and, therefore, can be used for the treatment of multidrug resistance.
Multidrug resistant protein 7 (MRP7; ABCC10), a member of MRP subfamily, is similar in topology to other MRPs (including MRP1) with two nucleotide-binding domains and three transmembrane domains (Kruh et al. (2007) Pflugers Arch. 453:675-84; Chen et al. (2003) Mol. Pharmacol. 63:351-58). ABCC10 is able to confer resistance to several natural product chemotherapeutic drugs, including taxanes and vinca alkaloids, which are also substrates of Pgp (Hopper-Borge et al. (2004) Cancer Res. 64:4927-30). ABCC10 has been reported to confer resistance to vinorelbine and paclitaxel in non-small cell lung cancer cells (Bessho et al. (2009) Oncol. Rep. 21:263-68; Oguri et al. (2008) Mol. Cancer. Ther. 7:1150-55) and to vincristine in human salivary gland adenocarcinoma cells (Naramoto et al. (2007) Int. J. Oncol. 30:393-401). The in vivo functions of ABCC10 have recently been confirmed using an Mrp7 knockout mouse model (Hopper-Borge et al. (2011) Cancer Res. 71(10):3649-57).
Phosphodiesterase type 5 (PDE5) inhibitors are widely used in the treatment of male erectile dysfunction and in improving breathing efficiency in pulmonary hypertension. As agents already used in the clinic for other purposes, these drugs were investigated for their effects on MDR and ABC transporters.